Colorectal cancer (CRC) is a common malignancy in Western countries. However, its frequency varies four-fold among US ethnic/racial minorities, with Japanese Americans (JAs) and African Americans (AAs) having a marked excess risk for the disease. Moreover, in contrast to JA patients who experience a better survival than whites, AAs with CRC present at a later stage and have a shorter, stage-adjusted survival than whites. The poor outcome of AA patients is not completely explained by their reduced access to medical care. These ethnic/racial disparities constitute an important public health challenge and also offer unique opportunities for etiologic research. This collaborative application will build upon the existing colorectal cancer Cooperative Family Registry (CFR) resource by recruiting additional families of AA (N=979) and Japanese (N=448) descent in Northern California, Southern California, North Carolina and Hawaii, using the CFR core protocol. We will then use the data and samples collected from a total of 1,514 AA, 745 JA and 750 white population-based families in the CFR to test the following hypotheses: 1) DNA mismatch repair deficiency is a more common pathogenic pathway to CRC in AAs, compared to whites, as reflected by a greater prevalence of tumor microsatellite instability (MSI); 2) Functional gene variants and environmental exposures related to chemical carcinogenesis and methyl group metabolism are associated with an increased risk of MSI-high CRC, particularly in AAs and JAs; 3) Functional variants in cell proliferation- and angiogenesis-related genes are associated with risk of advanced-stage CRC and poor overall survival, particularly in AAs; 4) Functional variants in genes related to response to 5-fluorouracil/oxaliplatin chemotherapy are associated with shorter disease-free and overall survival, especially in AA s; 5) Other gene variants that are rare in whites but relatively common in AAs and JAs are associated with CRC and may significantly contribute to the etiology of the disease in these groups. The power to test these hypotheses will not be adequate without the proposed expanded recruitment. The insight into biological pathways gained by this project may lead to new means of prevention and treatment that may help not only to alleviate health disparities in the US but also better control CRC among all ethnic/racial groups.